Research Departments & Organizations
We combine cell biology, genetics and mouse models to study lipid metabolism and cardiovascular related disorders. In particular, our research program aims to:
1. Identifying novel mechanisms by which cholesterol metabolism is regulated.
2. Assessing the contribution of non-coding RNA in regulating lipid metabolism.
3. Developing novel non-coding RNA based therapies for treating cardiovascular disorders.
Specialized Terms: Cholesterol homeostasis; Lipoprotein metabolism; Post-transcriptional regulation; microRNAs; Atherosclerosis; RNAi screening
Extensive Research Description
Our research aims to identify and characterize novel mechanisms by which cholesterol and lipoprotein metabolism is regulated. To date, most lipid and lipoprotein research has focused on alterations of protein coding genes, whereas the functions of non-coding RNAs remain largely unknown. Particular efforts are focused on microRNAs (miRNAs), a novel class of small non-coding RNAs that mediate port-transcriptional gene silencing. Using mouse models and cell culture studies, we will elucidate the molecular basis of the miRNA functions in regulating lipid metabolism and explore the potential of miRNAs as therapetic targets.
miRNAs have emerged as critical regulators of gene expression at the posttranscriptional level. miRNAs typically control the expression of their target genes by imperfect base pairing to the 3’ untranslated regions (3’UTR) of messenger RNAs (mRNAs) thereby inducing repression of the target mRNA. Bioinformatic predictions and experimental approaches indicate that a single miRNA may target more than a hundred mRNAs. Indeed, human miRNAs are predicted to control the activity of more than 60% of all protein-coding genes. This class of short (22 nucleotides) noncoding RNA molecules has been shown to participate in almost every cellular process investigated so far, and their dysregulation is observed in, and might underlie, different human pathologies including cancer, heart disease, and neurodegeneration. Very recently, we have demonstrated that miR-33, an intronic miRNA located within the SREBP-2 gene, plays important roles in the homeostatic regulation of cholesterol metabolism. miR-33 inhibits the expression of the ATP-binding cassette (ABC) transporter, ABCA1, thereby attenuating both cholesterol efflux to apoA1 and high-density lipoprotein (HDL) biogenesis. Conversely, silencing of miR-33 in vivo increased hepatic ABCA1 and plasma HDL. Because plasma HDL levels show a strong inverse correlation with atherosclerotic vascular disease, there has been intense interest in therapeutically targeting HDL and macrophage cholesterol efflux pathways. Our study suggests that antagonists of endogenous miR-33 may be a useful therapeutic strategy for enhancing ABCA1 expression and raising HDL levels in vivo. In addition, our recent preliminary data suggest that miR-33 also coordinates genes regulating fatty acid metabolism and insulin signaling. Therefore, we plan to continue investigating the potential relevance of miR-33 expression in metabolic syndrome. Moreover, we are working with other miRNAs involved in the regulation of cellular cholesterol homeostasis, and depending on the results, would pursue the most promising candidates in more detail.
A second major project is to characterize new genes involved in the regulation of cholesterol. A tightly controlled-but only partially characterized-network of cellular signaling and lipid transfer systems orchestrates the functional compartmentalization of cholesterol within and between tissues at the whole body level. Increased understanding of these processes and their integration at the organ systems level provides fundamental insights into the physiology of cholesterol metabolism. However several issues await further studies. For the most sterol transport processes, only a limited number of proteins that are involved have been identified and very little is known about cholesterol trafficking in many physiologically relevant cell types, such us hepatocytes, enterocytes or cells of the central nervous system. Future work will focus on determining the molecular mechanisms involved in the cholesterol metabolism in mammalian cells using functional genomic screens. Our current studies aim to identify new genes regulating low-density lipoprotein receptor activity and trafficking in human hepatic cell lines using a genome-wide RNA interference (RNAi) screens. Besides increasing our insights into the physiology of cholesterol trafficking, the information obtained should help to develop improved strategies for management of cholesterol-related pathologies.
- Role of Caveolin-1 in regulating lipoprotein metabolism and cardiovascular disorders.
- Regulation of lipid metabolism by microRNAs
- Identification of novel genes involved in the regulation cholesterol metabolism using genome-wide siRNAs screens
- Regulation of sterol metabolism by inflammation
Identification of Golgi-localized acyl transferases that palmitoylate and regulate endothelial nitric oxide synthase.
Fernández-Hernando C, Fukata M, Bernatchez PN, Fukata Y, Lin MI, Bredt DS, Sessa WC. Identification of Golgi-localized acyl transferases that palmitoylate and regulate endothelial nitric oxide synthase. The Journal Of Cell Biology 2006, 174:369-77. 2006
Loss of Akt1 leads to severe atherosclerosis and occlusive coronary artery disease.
Fernández-Hernando C, Ackah E, Yu J, Suárez Y, Murata T, Iwakiri Y, Prendergast J, Miao RQ, Birnbaum MJ, Sessa WC. Loss of Akt1 leads to severe atherosclerosis and occlusive coronary artery disease. Cell Metabolism 2007, 6:446-57. 2007
Genetic evidence supporting a critical role of endothelial caveolin-1 during the progression of atherosclerosis.
Fernández-Hernando C, Yu J, Suárez Y, Rahner C, Dávalos A, Lasunción MA, Sessa WC. Genetic evidence supporting a critical role of endothelial caveolin-1 during the progression of atherosclerosis. Cell Metabolism 2009, 10:48-54. 2009
MiR-33 contributes to the regulation of cholesterol homeostasis.
Rayner KJ, Suárez Y, Dávalos A, Parathath S, Fitzgerald ML, Tamehiro N, Fisher EA, Moore KJ, Fernández-Hernando C. MiR-33 contributes to the regulation of cholesterol homeostasis. Science (New York, N.Y.) 2010, 328:1570-3. 2010
miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling.
Dávalos A, Goedeke L, Smibert P, Ramírez CM, Warrier NP, Andreo U, Cirera-Salinas D, Rayner K, Suresh U, Pastor-Pareja JC, Esplugues E, Fisher EA, Penalva LO, Moore KJ, Suárez Y, Lai EC, Fernández-Hernando C. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108:9232-7. 2011
Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice.
Goedeke L, Salerno A, Ramírez CM, Guo L, Allen RM, Yin X, Langley SR, Esau C, Wanschel A, Fisher EA, Suárez Y, Baldán A, Mayr M, Fernández-Hernando C. Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice. EMBO Molecular Medicine 2014, 6:1133-41. 2014
MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels.
Goedeke L, Rotllan N, Canfrán-Duque A, Aranda JF, Ramírez CM, Araldi E, Lin CS, Anderson NN, Wagschal A, de Cabo R, Horton JD, Lasunción MA, Näär AM, Suárez Y, Fernández-Hernando C. MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. Nature Medicine 2015, 21:1280-9. 2015
ANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression.
Aryal B, Rotllan N, Araldi E, Ramírez CM, He S, Chousterman BG, Fenn AM, Wanschel A, Madrigal-Matute J, Warrier N, Martín-Ventura JL, Swirski FK, Suárez Y, Fernández-Hernando C. ANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression. Nature Communications 2016, 7:12313. 2016
Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages.
Araldi E, Fernández-Fuertes M, Canfrán-Duque A, Tang W, Cline GW, Madrigal-Matute J, Pober JS, Lasunción MA, Wu D, Fernández-Hernando C, Suárez Y. Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages. Cell Reports 2017, 19:2743-2755. 2017
Macrophage deficiency of miR-21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis.
Canfrán-Duque A, Rotllan N, Zhang X, Fernández-Fuertes M, Ramírez-Hidalgo C, Araldi E, Daimiel L, Busto R, Fernández-Hernando C, Suárez Y. Macrophage deficiency of miR-21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis. EMBO Molecular Medicine 2017, 9:1244-1262. 2017
Genetic Dissection of the Impact of miR-33a and miR-33b during the Progression of Atherosclerosis.
Price NL, Rotllan N, Canfrán-Duque A, Zhang X, Pati P, Arias N, Moen J, Mayr M, Ford DA, Baldán Á, Suárez Y, Fernández-Hernando C. Genetic Dissection of the Impact of miR-33a and miR-33b during the Progression of Atherosclerosis. Cell Reports 2017, 21:1317-1330. 2017
Genetic Ablation of miR-33 Increases Food Intake, Enhances Adipose Tissue Expansion, and Promotes Obesity and Insulin Resistance.
Price NL, Singh AK, Rotllan N, Goedeke L, Wing A, Canfrán-Duque A, Diaz-Ruiz A, Araldi E, Baldán Á, Camporez JP, Suárez Y, Rodeheffer MS, Shulman GI, de Cabo R, Fernández-Hernando C. Genetic Ablation of miR-33 Increases Food Intake, Enhances Adipose Tissue Expansion, and Promotes Obesity and Insulin Resistance. Cell Reports 2018, 22:2133-2145. 2018
Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis.
Aryal B, Singh AK, Zhang X, Varela L, Rotllan N, Goedeke L, Chaube B, Camporez JP, Vatner DF, Horvath TL, Shulman GI, Suárez Y, Fernández-Hernando C. Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis. JCI Insight 2018, 3. 2018